Ultrasound Obstet Gynecol 2014; 43: 681–686 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.13241
Predicting preterm birth in women with previous preterm birth and cervical length ≥ 25 mm A. G. CARE*, A. N. SHARP*, S. LANE†, D. ROBERTS‡, L. WATKINS‡ and Z. ALFIREVIC* *Centre for Women’s Health Research, University of Liverpool, Liverpool Women’s Hospital, Liverpool, UK; †Department of Biostatistics, University of Liverpool, Shelleys Cottage, Liverpool, UK; ‡Liverpool Women’s Hospital, Liverpool, UK
K E Y W O R D S: cervix; prediction; pregnancy; preterm birth; transvaginal ultrasound
ABSTRACT
INTRODUCTION
Objective To identify risk factors predicting subsequent spontaneous preterm birth or preterm prelabor rupture of membranes (PPROM) in a cohort of women with a history of spontaneous preterm birth and a cervical length of ≥ 25 mm at 20–24 weeks’ gestation.
Preterm birth continues to be the leading cause of perinatal morbidity and mortality worldwide1 . Prediction and prevention of spontaneous preterm birth remain challenging priorities for obstetricians globally2 . It has been hypothesized that spontaneous preterm birth can be caused by several etiologies resulting in a final common pathway of shortening the cervix as the terminal event prior to preterm delivery or preterm prelabor rupture of membranes (PPROM)3 . Numerous studies have clearly demonstrated that the relationship between a sonographic short cervix and spontaneous preterm birth is most sensitive when combining cervical length and obstetric history in high-risk populations with previous preterm birth4 – 11 . A cut-off value of cervical length of 25 mm has been used by clinicians and researchers to screen for women at the highest risk of spontaneous preterm birth12 – 15 . Recently, this group of women has been targeted with interventions to reduce the risk of spontaneous preterm birth including vaginal progesterone16 , cerclage17 and cervical pessary14 . In addition, current practice guidelines recommend initiation of therapy in high-risk patients with a cervical length of < 25 mm in the midtrimester18 – 20 . Notwithstanding this, the risks for women with a previous spontaneous preterm birth with a normal cervix in pregnancy may not be negligible. A study by Celik et al.21 screened a general population and suggested that there is a continuum of risk dependent on absolute cervical length, for example with a midtrimester cervical length of 26 mm, the preterm birth rate is 20%, compared with only 6% when cervical length is 40 mm21 . On the other hand, a secondary analysis of a randomized study by Owen et al.22 showed that absolute length of cervix above 25 mm had little impact on the risk of preterm birth before 35 weeks, which appeared to be stable at 16% across different cervical lengths > 25 mm. However, the
Methods We identified all pregnant women who attended our preterm labor clinic between January 2010 and December 2012 because of previous spontaneous preterm birth or PPROM before 34 weeks. Women with a normal cervical length (defined as ≥ 25 mm) between 20 and 24 weeks’ gestation were identified and included in the analysis. Maternal characteristics, obstetric history, shortest cervical length and gestational age at shortest cervical length of women who delivered preterm (before 37 weeks) were compared with those who delivered at or after 37 weeks in the index pregnancy. Multiple regression analysis was planned to examine the relationship between significant clinical and cervical-length variables to identify significant clinical predictors of spontaneous preterm birth among high-risk patients with a normal cervix between 20 and 24 weeks’ gestation. Results Of 134 women with a normal cervix at 20–24 weeks, 28 (20.9%) delivered spontaneously or had PPROM before 37 weeks; of these 12 (9.0%) delivered before 34 weeks. None of the selected explanatory variables was predictive of recurrent preterm birth in this cohort. No correlation between absolute cervical length and gestational age at delivery was found (R = 0.01). Conclusion In high-risk women with a cervical length of ≥ 25 mm at 20–24 weeks’ gestation, demographic characteristics and absolute cervical length are not useful in predicting subsequent spontaneous preterm birth. Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
Correspondence to: Dr A. G. Care, Centre for Women’s Health Research, Liverpool Women’s Hospital, Crown Street, Liverpool, L8 7SS, UK (e-mail: [email protected]) Accepted: 16 October 2013
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
ORIGINAL PAPER
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authors were unable to differentiate between spontaneous and iatrogenic preterm birth22 . The question, therefore, remains how best to identify these high-risk women who will have preterm birth despite normal cervical length in the midtrimester. Our aim was to identify any clinical risk factors or characteristics predicting spontaneous preterm birth/PPROM in this subgroup of women with a sonographic long cervix at the midtrimester.
PATIENTS AND METHODS All women who attended the preterm labor clinic at the Liverpool Women’s Hospital, UK, who delivered between January 2010 and December 2012, were identified and their data were extracted from a database of continuous service evaluation collected prospectively. Details of the outpatient management of women attending this clinic have been published previously13 . Only women with a previous spontaneous preterm birth or PPROM between 16 + 0 and 34 + 0 weeks’ gestation and a cervical length of ≥ 25 mm between 20 and 24 weeks were included in this analysis. Women with previous cervical surgery (n = 93), previous or current iatrogenic preterm birth (n = 19) or history that indicated cerclage (n = 18) were excluded (Figure 1). Fifteen women classified as ‘other exclusions’ included: uterine anomalies (n = 2), Ehlers–Danlos syndrome (n = 1), intrauterine death (n = 3), twins (n = 1), termination of pregnancy owing to congenital abnormalities (n = 2), inevitable miscarriage at first visit (n = 1) and loss to follow-up (n = 5). Age, ethnicity, parity, height, weight, body mass index (BMI), number and gestation of previous preterm births or PPROM, shortest cervical length measurement and gestational age when shortest cervical length was measured (of women who delivered at term) were compared with those who delivered spontaneously preterm (defined as before 37 weeks). Late spontaneous preterm birth (i.e. at 34 + 0 to 36 + 6 weeks) account for over half of late preterm births and is the leading cause of admission to neonatal intensive care23 , though rates of perinatal morbidity and mortality remain highest in babies born before 34 + 0 weeks, and it is recommended practice to deliver patients with PPROM after this time point24 . Therefore subanalysis was performed on women who delivered before 34 weeks compared to those who delivered after 37 weeks. P-values were calculated using the independent sample t-test, Mann–Whitney U-test, chi square test or Fisher’s exact test as appropriate. Multiple regression analysis was planned to examine the relationship between positive clinical and cervical length variables and the likelihood of preterm birth. The small sample size limited the multiple regression model to a maximum of four explanatory variables (BMI, cervical length, gestational age of previous preterm birth and number of previous deliveries). Finally, an examination of the correlation between cervical length measurements performed between 20 + 0 and 24 + 6 weeks’ gestation and gestational age at birth was planned.
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
It has previously been demonstrated that the predictive performance of cervical length measurement is greater the closer the sonographic examination is performed to 24 weeks8 . Therefore when multiple cervical measurements were taken between 20 + 0 and 24 + 6 weeks, the measurement closest to 24 weeks was utilized for analysis. The statistical software package SPSS Statistics for Windows, Version 20.0 (IBM Corp. Armonk, NY, USA) was used for all data analysis.
RESULTS Of the 196 women who attended the preterm labor clinic with a previous history of spontaneous preterm birth or PPROM between 16 + 0 and 34 + 0 weeks’ gestation, 134 (68.4%) had a midtrimester sonographic cervical length of ≥ 25 mm and, therefore, did not receive any treatment. The overall preterm birth rate in this group was 20.9% (Figure 1). Table 1 presents an overview of maternal characteristics and pregnancy outcomes. Of 28 women with recorded preterm birth, 17 (60.7%) had spontaneous labor and the remaining 11 (39.3%) had PPROM, eight of whom had induction of labor, and three women required Cesarean section (breech presentation, previous Cesarean section and placenta previa). Twelve women delivered before 34 weeks (42.9%) and four before 28 weeks (14.3%). Neonates born preterm had a lower mean birth weight, a higher rate of admission to Level-2 special care baby unit (75% vs 5.9%), greater ventilation requirements (32.1% vs 5.9%) and a higher rate of respiratory distress syndrome (25% vs 1.0%). There was no statistical difference in maternal age, height, weight or BMI between women who subsequently delivered preterm and those delivering at term. There was no difference when known risk factors for preterm birth were analyzed; smoking, BMI, number of previous preterm births and gestational age at which the previous preterm birth occurred. Univariate regression analysis failed to identify any statistically significant explanatory variables (data not shown) and, therefore, multiple regression analysis was not performed. There was no correlation between cervical length at 20–24 weeks and gestational outcome at delivery (R = 0.01) (Figure 2).
DISCUSSION This study has not identified any clinical or obstetric risk factors in high-risk women with a cervical length greater than 25 mm that could help to identify those who will subsequently have a spontaneous preterm birth. Iams et al.25 hypothesized that pathological cervical shortening begins before 24 weeks’ gestation, following evaluation of the rate of change of cervical length between 24 weeks and 28 weeks in patients with subsequent spontaneous preterm delivery (preterm labor or PPROM) compared with those with iatrogenic preterm delivery and/or term
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Women with data in preterm labor clinic database who delivered between January 2010 and December 2012 (n = 397)
Excluded (n = 201): Referred for previous cervical surgery (LEEP/knife cone biopsy) (n = 93) Symptomatic preterm labor (n = 9) Previous or current PTB not spontaneous (e.g. abruption) (n = 19) Inappropriate referral (n = 15) History that indicated cerclage (n = 18) No TVS at 20–24 weeks (i.e. TVS before 20 or after 24 weeks only) (n = 32) Other (n = 15)
Previous sPTB/PPROM before 34 weeks (n = 196)
Treated for short cervix (n = 62) (31.6%)
Term delivery* (n = 37) (59.7%)
Preterm delivery† (n = 25) (40.3%)
Cervical length ≥ 25 mm at 20–24 weeks (n = 134) (68.4%)
Term delivery* (n = 106) (79.1%)
PTB/PPROM before 34 weeks (n = 20/62) (32.3%)
Preterm delivery† (n = 28) (20.9%)
PTB/PPROM before 34 weeks (n = 12/134) (9.0%)
Figure 1 Flow-chart for women included in the study. *Term delivery defined as delivery at or after 37 weeks’ gestation. †Preterm delivery defined as delivery before 37 weeks. LEEP, loop electrosurgical excision procedure; PPROM, preterm prelabor rupture of membranes; PTB, preterm birth; sPTB, spontaneous PTB; TVS, transvaginal sonography.
delivery. They found that the average rate of change in cervical length per week was significantly higher in those with spontaneous preterm birth or PPROM than was that of the control groups, at −0.96 mm/week (spontaneous preterm birth) or −0.82 mm/week (PPROM)25 . This steady state of decline in cervical length was not seen in our cohort. Although follow-up was considered too variable in both number and scan interval to allow formal analysis on rates of change of cervical length between our cohorts, data are available for the most recent cervical length before delivery. Four women delivered at 27 weeks’ gestation despite normal cervical lengths measured between 20 and 24 weeks. Two of these four women had cervical length measurements in the preterm labor clinic 6 days before preterm delivery and were found to have cervical lengths of 32 and 30 mm, respectively, suggesting a much more acute cervical shortening process. The study by Iams et al.25 excluded women delivering before 28 weeks, which may be one reason why a much more rapid rate of decline in cervical length was not reported. Using a secondary analysis of a randomized trial comparing no treatment vs cerclage in a population of women with a short cervix (< 25 mm), Owen et al.22 suggested that a cervical length equal to or greater than 25 mm measured between 16 + 0 and 22 + 6 weeks does not predict length of gestation in women with previous preterm birth. The rate of preterm birth in their cohort with a cervical length of at least 25 mm was 16%, which is comparable with the 20% reported in our study. However, in their study the cohort of women with a
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
cervical length of at least 25 mm did not have follow-up data regarding the use of progesterone or type of preterm birth (spontaneous or iatrogenic) and, therefore, a more detailed analysis was not possible. It was assumed that the majority of these births would be spontaneous, as few had risk factors for iatrogenic delivery. Other than a short cervical length, the strongest predicting factors for spontaneous preterm birth are a prior spontaneous preterm birth, Black race and a low BMI26 . In our predominantly White cohort (a reflection of the current background population of Liverpool, North West England (88.8% White))27 , neither gestational age at time of previous preterm birth (P = 0.22–0.99), BMI (P = 0.15) nor ethnicity acted as predictive factors (Table 1). Myometrial contractility, decidual activation and cervical ripening are the key elements of parturition28 . Relatively slow, progressive ripening and shortening of the cervix is thought to be the detectable phenotype of a final common pathway of various underlying pathologies such as intra-amniotic infection29 , abnormal progesterone action30 , cervical surgery31 and cervical insufficiency32 . We suggest that there appears to be an additional phenotype of preterm birth with a rapid shortening of the cervix, not detected by 20–24-week cervical length screening. This may reflect dysfunctionality in decidual activation or myometrial contractility, leading to accelerated cervical shortening or a more rapid variant of the known causes of premature cervical ripening.
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Table 1 Characteristics and pregnancy outcome of women with a previous spontaneous preterm labor or preterm prelabor rupture of membranes and cervical length ≥ 25 mm according to delivery at term or at < 37 weeks or < 34 weeks’ gestation
Parameter Maternal characteristics Age (years) Height (cm) Weight (kg) Body mass index (kg/m2 ) Smoker Race/ethnicity White Black African Asian Arab Chinese Other Parity Total previous PTB Previous PTB/PPROM at 16 + 0 to 23 + 6 weeks Previous PTB/PPROM at 24 + 0 to 28 + 6 weeks Previous PTB/PPROM at 29 + 0 to 34 + 0 weeks Shortest cervical length (mm) Gestational age when shortest cervical length recorded Neonatal outcomes§ Birth weight (g) Admission to special care baby unit Apgar score < 7 at 5 min Ventilatory support required Respiratory distress syndrome Necrotising enterocolitis Retinopathy of prematurity Intraventricular hemorrhage/periventricular leukomalacia Number of days in Level-2 special care baby unit Neonatal death (within 28 days)
Delivery at term (n = 106)
Delivery < 37 weeks (n = 28)
30.0 ± 5.4 164.0 ± 6.8 68.9 ± 16.9 25.6 ± 6.0 29 (27.4)
30.8 ± 7.0 165.3 ± 5.4 75.6 ± 20.2 27.5 ± 6.6 6 (21.4)
92 (86.8) 3 (2.8) 4 (3.8) 2 (1.9) 2 (1.9) 3 (2.8) 1 [1] 121 25 (20.7) 35 (28.9) 61 (50.4) 33 [5] 23 [5]
27 (96.4) 0 1 (3.6) 0 0 0 1 [1] 31 1 (3.2) 11 (35.5) 19 (61.3) 33 [6] 26 [5]
3288 ± 645 6 (5.9) 3 (3.0) 6 (5.9) 1 (1.0) 0 0 0 0 0
2240 ± 616 21 (75.0) 3 (10.7) 9 (32.1) 7 (25.0) 0 0 0 1.1 ± 2.6 0
P 0.44* 0.2* 0.11* 0.15* 0.51† N/A
Delivery < 34 weeks (n = 12) 31.8 ± 7.4 165.5 ± 5.6 79.1 ± 21.2 28.6 ± 6.5 1 (8.3)
P 0.36* 0.44* 0.09* 0.08* 0.15‡ N/A
N/A N/A 0.22† 0.99† 0.34† 0.9* 0.18*
12 (100) 0 0 0 0 0 1 [1] 12 0 5 (41.7) 7 (58.3) 31.5 [6.5] 23 [6.5]
N/A N/A 0.46‡ 0.99‡ 0.58‡ 0.08* 0.80*
< 0.001† < 0.001† < 0.09† < 0.001† < 0.001† N/A N/A N/A N/A N/A
1727 ± 521 12 (100) 1 (8.3) 6 (50) 4 (33.3) 0 0 0 2.7 ± 3.7 0
< 0.001* < 0.001‡ 0.37‡ < 0.001‡ < 0.001‡ N/A N/A N/A N/A N/A
Data presented as mean ± SD, n, n (%) or median [interquartile range]. *Mann–Whitney U-test. †Chi-square test. ‡Fisher’s exact test. §Five in term group and one in preterm group lost to follow-up. N/A, not applicable; PTB, preterm birth; PPROM, preterm prelabor rupture of membranes.
We acknowledge that bacterial vaginosis and fetal fibronectin, two potentially powerful predictors of preterm birth, were not tested in our cohort. A Cochrane review of three trials with 421 participants in total showed that, in women with a previous preterm birth and asymptomatic bacterial vaginosis, antibiotic treatment did not significantly reduce the risk of subsequent preterm birth (absolute risk reduction, 0.78 (95% CI, 0.42–1.48))33 . Therefore, our policy to date has been not to perform bacterial vaginosis screening for asymptomatic women in our preterm labor clinic. Fetal fibronectin testing has shown to be most accurate in predicting imminent spontaneous preterm birth among symptomatic women34 . In a systematic review by Honest et al.34 , the diagnostic accuracy of fetal fibronectin in high-risk asymptomatic women varied greatly. The median likelihood ratio for predicting spontaneous preterm birth before 34 weeks’ gestation among the five highest-quality studies was 3.99 (interquartile range, 1.73–10.18). In our clinic population, with an average pretest probability of preterm birth of 26%, a positive fetal fibronectin test would increase the risk of preterm birth to 58.4%. Although this is certainly
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
promising, this interpretation may not be applicable to a subgroup of high-risk women with a long cervix. The usefulness of fetal fibronectin testing is further limited by the lack of proven successful treatment interventions in this cohort. This is an area that requires further research, and we eagerly await the findings of the OPPTIMUM trial of prophylactic progesterone to prevent preterm birth in fetal fibronectin-positive women35 . Limitations of this study include the relatively small sample size and predominantly White British population demographic. We had been looking for strong associations that are clinically important on an individual patient level in an attempt to identify those women with a long cervix at risk of preterm birth. However, our negative findings may be influenced by the small sample size, and it is possible that these findings would not be replicated in a larger cohort. Additionally caution should be exercised before applying these results to other geographical locations, particularly in areas with a higher representation of Black race, a known risk factor for preterm birth1 . Out of 196 high-risk women screened in our clinic, 12 (6.1%) had a preterm birth before 34 weeks’ gestation,
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Gestational age at delivery (weeks)
45
40
35
30
25 20
30 40 50 Cervical length at 20–24 weeks (mm)
60
Figure 2 Scatterplot of midtrimester cervical length measurement against gestational age at delivery in a cohort of 196 women with a history of spontaneous preterm birth or preterm prelabor rupture of membranes before 34 weeks’ gestation.
despite persistently normal cervical length measurements. If we are to make progress in ameliorating the global burden of spontaneous preterm birth, we should move away from a short cervix as the only clinically useful ‘biomarker’ for all pathologies of preterm birth. We need to focus on a better understanding and identification of mechanisms behind the multitude of etiologies causing this syndrome. Only through such research will we be able to develop more effective screening and treatment strategies that could be applied to both high- and low-risk populations. Suggested ways forward would be: (1) to continue with the search for alternative biomarkers in blood, amniotic fluid or vaginal secretions to aid our understanding of pathways of action36 ; (2) to explore genetic association studies, a major tool for identifying genes conferring susceptibility to disorders in which both genetic and environmental factors contribute to susceptibility risk37,38 ; and (3) to understand how to link this new information together to provide individual patient-risk assessment. Until more robust, personalized predictive models are developed, cervical length will remain our best clinical marker in high-risk asymptomatic women. However, for a significant number of high-risk women, a long cervix will provide false reassurance against recurrent preterm birth and its sequelae.
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686 18. Committee on Practice Bulletins – Obstetrics, The American College of Obstetricians and Gynecologists. Practice bulletin no. 130: prediction and prevention of preterm birth. Obstet Gynecol 2012; 120: 964–973. 19. Berghella V. Universal cervical length screening for prediction and prevention of preterm birth. Obstet Gynecol Surv 2012; 67: 653–658. 20. Lim K, Butt K, Crane JM. SOGC Clinical Practice Guideline. Ultrasonographic cervical length assessment in predicting preterm birth in singleton pregnancies. J Obstet Gynaecol Can 2011; 33: 486–499. 21. Celik E, To M, Gajewska K, Smith G, Nicolaides K. Cervical Length and obstetric history predict spontaneous preterm birth: development and validation model to provide individualized risk assessment. Ultrasound Obstet Gynecol 2008; 31:549–554. 22. Owen J, Szychowski JM, Hankins G, Iams JD, Sheffield JS, Perez-Delboy A, Berghella V, Wing DA, Guzman ER; Vaginal Ultrasound Trial Consortium. Does midtrimester cervical length ≥ 25 mm predict preterm birth in high-risk women? Am J Obstet Gynecol 2010; 203: 393.e1–5. 23. Laughon SK, Reddy UM, Sun L, Zhang J. Precursors for late preterm birth in singleton gestations. Obstet Gynecol 2010; 116: 1047–1055. 24. Mercer BM. Preterm premature rupture of the membranes. In Preterm Birth: Prevention and Management, Berghella V (ed.). Wiley-Blackwell: New York, NY, 2010; 223–224. 25. Iams JD, Cebrik D, Lynch C, Behrendt N, Das A. The rate of cervical change and the phenotype of spontaneous preterm birth. Am J Obstet Gynecol 2011; 205: 130.e1–6. 26. Goldenberg RL, Iams JD, Mercer BM, Meis PJ, Moawad AH, Copper RL, Das A, Thom E, Johnson F, McNellis D, Miodovnik M, Van Dorsten JP, Caritis SN, Thurnau GR, Bottoms SF. The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births. NICHD MFMU Network. Am J Public Health 1998; 88: 233–238. 27. The Office of National Statistics, 2011. Updated: 2011 Census – Ethnicity [online] Available at: http://www.ons.gov.uk/ ons/interactive/census-map-2-1–ethnicity/index.html [Accessed September 18th 2013]. 28. Romero R, Lockwood C. Pathogenesis of spontaneous preterm labour. W. B. Saunders: Philadelphia, PA, 2009.
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Predicting preterm birth in women with previous preterm birth and cervical length ≥ 25 mm A. G. CARE*, A. N. SHARP*, S. LANE†, D. ROBERTS‡, L. WATKINS‡ and Z. ALFIREVIC* *Centre for Women’s Health Research, University of Liverpool, Liverpool Women’s Hospital, Liverpool, UK; †Department of Biostatistics, University of Liverpool, Shelleys Cottage, Liverpool, UK; ‡Liverpool Women’s Hospital, Liverpool, UK
K E Y W O R D S: cervix; prediction; pregnancy; preterm birth; transvaginal ultrasound
ABSTRACT
INTRODUCTION
Objective To identify risk factors predicting subsequent spontaneous preterm birth or preterm prelabor rupture of membranes (PPROM) in a cohort of women with a history of spontaneous preterm birth and a cervical length of ≥ 25 mm at 20–24 weeks’ gestation.
Preterm birth continues to be the leading cause of perinatal morbidity and mortality worldwide1 . Prediction and prevention of spontaneous preterm birth remain challenging priorities for obstetricians globally2 . It has been hypothesized that spontaneous preterm birth can be caused by several etiologies resulting in a final common pathway of shortening the cervix as the terminal event prior to preterm delivery or preterm prelabor rupture of membranes (PPROM)3 . Numerous studies have clearly demonstrated that the relationship between a sonographic short cervix and spontaneous preterm birth is most sensitive when combining cervical length and obstetric history in high-risk populations with previous preterm birth4 – 11 . A cut-off value of cervical length of 25 mm has been used by clinicians and researchers to screen for women at the highest risk of spontaneous preterm birth12 – 15 . Recently, this group of women has been targeted with interventions to reduce the risk of spontaneous preterm birth including vaginal progesterone16 , cerclage17 and cervical pessary14 . In addition, current practice guidelines recommend initiation of therapy in high-risk patients with a cervical length of < 25 mm in the midtrimester18 – 20 . Notwithstanding this, the risks for women with a previous spontaneous preterm birth with a normal cervix in pregnancy may not be negligible. A study by Celik et al.21 screened a general population and suggested that there is a continuum of risk dependent on absolute cervical length, for example with a midtrimester cervical length of 26 mm, the preterm birth rate is 20%, compared with only 6% when cervical length is 40 mm21 . On the other hand, a secondary analysis of a randomized study by Owen et al.22 showed that absolute length of cervix above 25 mm had little impact on the risk of preterm birth before 35 weeks, which appeared to be stable at 16% across different cervical lengths > 25 mm. However, the
Methods We identified all pregnant women who attended our preterm labor clinic between January 2010 and December 2012 because of previous spontaneous preterm birth or PPROM before 34 weeks. Women with a normal cervical length (defined as ≥ 25 mm) between 20 and 24 weeks’ gestation were identified and included in the analysis. Maternal characteristics, obstetric history, shortest cervical length and gestational age at shortest cervical length of women who delivered preterm (before 37 weeks) were compared with those who delivered at or after 37 weeks in the index pregnancy. Multiple regression analysis was planned to examine the relationship between significant clinical and cervical-length variables to identify significant clinical predictors of spontaneous preterm birth among high-risk patients with a normal cervix between 20 and 24 weeks’ gestation. Results Of 134 women with a normal cervix at 20–24 weeks, 28 (20.9%) delivered spontaneously or had PPROM before 37 weeks; of these 12 (9.0%) delivered before 34 weeks. None of the selected explanatory variables was predictive of recurrent preterm birth in this cohort. No correlation between absolute cervical length and gestational age at delivery was found (R = 0.01). Conclusion In high-risk women with a cervical length of ≥ 25 mm at 20–24 weeks’ gestation, demographic characteristics and absolute cervical length are not useful in predicting subsequent spontaneous preterm birth. Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
Correspondence to: Dr A. G. Care, Centre for Women’s Health Research, Liverpool Women’s Hospital, Crown Street, Liverpool, L8 7SS, UK (e-mail: [email protected]) Accepted: 16 October 2013
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
ORIGINAL PAPER
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authors were unable to differentiate between spontaneous and iatrogenic preterm birth22 . The question, therefore, remains how best to identify these high-risk women who will have preterm birth despite normal cervical length in the midtrimester. Our aim was to identify any clinical risk factors or characteristics predicting spontaneous preterm birth/PPROM in this subgroup of women with a sonographic long cervix at the midtrimester.
PATIENTS AND METHODS All women who attended the preterm labor clinic at the Liverpool Women’s Hospital, UK, who delivered between January 2010 and December 2012, were identified and their data were extracted from a database of continuous service evaluation collected prospectively. Details of the outpatient management of women attending this clinic have been published previously13 . Only women with a previous spontaneous preterm birth or PPROM between 16 + 0 and 34 + 0 weeks’ gestation and a cervical length of ≥ 25 mm between 20 and 24 weeks were included in this analysis. Women with previous cervical surgery (n = 93), previous or current iatrogenic preterm birth (n = 19) or history that indicated cerclage (n = 18) were excluded (Figure 1). Fifteen women classified as ‘other exclusions’ included: uterine anomalies (n = 2), Ehlers–Danlos syndrome (n = 1), intrauterine death (n = 3), twins (n = 1), termination of pregnancy owing to congenital abnormalities (n = 2), inevitable miscarriage at first visit (n = 1) and loss to follow-up (n = 5). Age, ethnicity, parity, height, weight, body mass index (BMI), number and gestation of previous preterm births or PPROM, shortest cervical length measurement and gestational age when shortest cervical length was measured (of women who delivered at term) were compared with those who delivered spontaneously preterm (defined as before 37 weeks). Late spontaneous preterm birth (i.e. at 34 + 0 to 36 + 6 weeks) account for over half of late preterm births and is the leading cause of admission to neonatal intensive care23 , though rates of perinatal morbidity and mortality remain highest in babies born before 34 + 0 weeks, and it is recommended practice to deliver patients with PPROM after this time point24 . Therefore subanalysis was performed on women who delivered before 34 weeks compared to those who delivered after 37 weeks. P-values were calculated using the independent sample t-test, Mann–Whitney U-test, chi square test or Fisher’s exact test as appropriate. Multiple regression analysis was planned to examine the relationship between positive clinical and cervical length variables and the likelihood of preterm birth. The small sample size limited the multiple regression model to a maximum of four explanatory variables (BMI, cervical length, gestational age of previous preterm birth and number of previous deliveries). Finally, an examination of the correlation between cervical length measurements performed between 20 + 0 and 24 + 6 weeks’ gestation and gestational age at birth was planned.
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
It has previously been demonstrated that the predictive performance of cervical length measurement is greater the closer the sonographic examination is performed to 24 weeks8 . Therefore when multiple cervical measurements were taken between 20 + 0 and 24 + 6 weeks, the measurement closest to 24 weeks was utilized for analysis. The statistical software package SPSS Statistics for Windows, Version 20.0 (IBM Corp. Armonk, NY, USA) was used for all data analysis.
RESULTS Of the 196 women who attended the preterm labor clinic with a previous history of spontaneous preterm birth or PPROM between 16 + 0 and 34 + 0 weeks’ gestation, 134 (68.4%) had a midtrimester sonographic cervical length of ≥ 25 mm and, therefore, did not receive any treatment. The overall preterm birth rate in this group was 20.9% (Figure 1). Table 1 presents an overview of maternal characteristics and pregnancy outcomes. Of 28 women with recorded preterm birth, 17 (60.7%) had spontaneous labor and the remaining 11 (39.3%) had PPROM, eight of whom had induction of labor, and three women required Cesarean section (breech presentation, previous Cesarean section and placenta previa). Twelve women delivered before 34 weeks (42.9%) and four before 28 weeks (14.3%). Neonates born preterm had a lower mean birth weight, a higher rate of admission to Level-2 special care baby unit (75% vs 5.9%), greater ventilation requirements (32.1% vs 5.9%) and a higher rate of respiratory distress syndrome (25% vs 1.0%). There was no statistical difference in maternal age, height, weight or BMI between women who subsequently delivered preterm and those delivering at term. There was no difference when known risk factors for preterm birth were analyzed; smoking, BMI, number of previous preterm births and gestational age at which the previous preterm birth occurred. Univariate regression analysis failed to identify any statistically significant explanatory variables (data not shown) and, therefore, multiple regression analysis was not performed. There was no correlation between cervical length at 20–24 weeks and gestational outcome at delivery (R = 0.01) (Figure 2).
DISCUSSION This study has not identified any clinical or obstetric risk factors in high-risk women with a cervical length greater than 25 mm that could help to identify those who will subsequently have a spontaneous preterm birth. Iams et al.25 hypothesized that pathological cervical shortening begins before 24 weeks’ gestation, following evaluation of the rate of change of cervical length between 24 weeks and 28 weeks in patients with subsequent spontaneous preterm delivery (preterm labor or PPROM) compared with those with iatrogenic preterm delivery and/or term
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Women with data in preterm labor clinic database who delivered between January 2010 and December 2012 (n = 397)
Excluded (n = 201): Referred for previous cervical surgery (LEEP/knife cone biopsy) (n = 93) Symptomatic preterm labor (n = 9) Previous or current PTB not spontaneous (e.g. abruption) (n = 19) Inappropriate referral (n = 15) History that indicated cerclage (n = 18) No TVS at 20–24 weeks (i.e. TVS before 20 or after 24 weeks only) (n = 32) Other (n = 15)
Previous sPTB/PPROM before 34 weeks (n = 196)
Treated for short cervix (n = 62) (31.6%)
Term delivery* (n = 37) (59.7%)
Preterm delivery† (n = 25) (40.3%)
Cervical length ≥ 25 mm at 20–24 weeks (n = 134) (68.4%)
Term delivery* (n = 106) (79.1%)
PTB/PPROM before 34 weeks (n = 20/62) (32.3%)
Preterm delivery† (n = 28) (20.9%)
PTB/PPROM before 34 weeks (n = 12/134) (9.0%)
Figure 1 Flow-chart for women included in the study. *Term delivery defined as delivery at or after 37 weeks’ gestation. †Preterm delivery defined as delivery before 37 weeks. LEEP, loop electrosurgical excision procedure; PPROM, preterm prelabor rupture of membranes; PTB, preterm birth; sPTB, spontaneous PTB; TVS, transvaginal sonography.
delivery. They found that the average rate of change in cervical length per week was significantly higher in those with spontaneous preterm birth or PPROM than was that of the control groups, at −0.96 mm/week (spontaneous preterm birth) or −0.82 mm/week (PPROM)25 . This steady state of decline in cervical length was not seen in our cohort. Although follow-up was considered too variable in both number and scan interval to allow formal analysis on rates of change of cervical length between our cohorts, data are available for the most recent cervical length before delivery. Four women delivered at 27 weeks’ gestation despite normal cervical lengths measured between 20 and 24 weeks. Two of these four women had cervical length measurements in the preterm labor clinic 6 days before preterm delivery and were found to have cervical lengths of 32 and 30 mm, respectively, suggesting a much more acute cervical shortening process. The study by Iams et al.25 excluded women delivering before 28 weeks, which may be one reason why a much more rapid rate of decline in cervical length was not reported. Using a secondary analysis of a randomized trial comparing no treatment vs cerclage in a population of women with a short cervix (< 25 mm), Owen et al.22 suggested that a cervical length equal to or greater than 25 mm measured between 16 + 0 and 22 + 6 weeks does not predict length of gestation in women with previous preterm birth. The rate of preterm birth in their cohort with a cervical length of at least 25 mm was 16%, which is comparable with the 20% reported in our study. However, in their study the cohort of women with a
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
cervical length of at least 25 mm did not have follow-up data regarding the use of progesterone or type of preterm birth (spontaneous or iatrogenic) and, therefore, a more detailed analysis was not possible. It was assumed that the majority of these births would be spontaneous, as few had risk factors for iatrogenic delivery. Other than a short cervical length, the strongest predicting factors for spontaneous preterm birth are a prior spontaneous preterm birth, Black race and a low BMI26 . In our predominantly White cohort (a reflection of the current background population of Liverpool, North West England (88.8% White))27 , neither gestational age at time of previous preterm birth (P = 0.22–0.99), BMI (P = 0.15) nor ethnicity acted as predictive factors (Table 1). Myometrial contractility, decidual activation and cervical ripening are the key elements of parturition28 . Relatively slow, progressive ripening and shortening of the cervix is thought to be the detectable phenotype of a final common pathway of various underlying pathologies such as intra-amniotic infection29 , abnormal progesterone action30 , cervical surgery31 and cervical insufficiency32 . We suggest that there appears to be an additional phenotype of preterm birth with a rapid shortening of the cervix, not detected by 20–24-week cervical length screening. This may reflect dysfunctionality in decidual activation or myometrial contractility, leading to accelerated cervical shortening or a more rapid variant of the known causes of premature cervical ripening.
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Table 1 Characteristics and pregnancy outcome of women with a previous spontaneous preterm labor or preterm prelabor rupture of membranes and cervical length ≥ 25 mm according to delivery at term or at < 37 weeks or < 34 weeks’ gestation
Parameter Maternal characteristics Age (years) Height (cm) Weight (kg) Body mass index (kg/m2 ) Smoker Race/ethnicity White Black African Asian Arab Chinese Other Parity Total previous PTB Previous PTB/PPROM at 16 + 0 to 23 + 6 weeks Previous PTB/PPROM at 24 + 0 to 28 + 6 weeks Previous PTB/PPROM at 29 + 0 to 34 + 0 weeks Shortest cervical length (mm) Gestational age when shortest cervical length recorded Neonatal outcomes§ Birth weight (g) Admission to special care baby unit Apgar score < 7 at 5 min Ventilatory support required Respiratory distress syndrome Necrotising enterocolitis Retinopathy of prematurity Intraventricular hemorrhage/periventricular leukomalacia Number of days in Level-2 special care baby unit Neonatal death (within 28 days)
Delivery at term (n = 106)
Delivery < 37 weeks (n = 28)
30.0 ± 5.4 164.0 ± 6.8 68.9 ± 16.9 25.6 ± 6.0 29 (27.4)
30.8 ± 7.0 165.3 ± 5.4 75.6 ± 20.2 27.5 ± 6.6 6 (21.4)
92 (86.8) 3 (2.8) 4 (3.8) 2 (1.9) 2 (1.9) 3 (2.8) 1 [1] 121 25 (20.7) 35 (28.9) 61 (50.4) 33 [5] 23 [5]
27 (96.4) 0 1 (3.6) 0 0 0 1 [1] 31 1 (3.2) 11 (35.5) 19 (61.3) 33 [6] 26 [5]
3288 ± 645 6 (5.9) 3 (3.0) 6 (5.9) 1 (1.0) 0 0 0 0 0
2240 ± 616 21 (75.0) 3 (10.7) 9 (32.1) 7 (25.0) 0 0 0 1.1 ± 2.6 0
P 0.44* 0.2* 0.11* 0.15* 0.51† N/A
Delivery < 34 weeks (n = 12) 31.8 ± 7.4 165.5 ± 5.6 79.1 ± 21.2 28.6 ± 6.5 1 (8.3)
P 0.36* 0.44* 0.09* 0.08* 0.15‡ N/A
N/A N/A 0.22† 0.99† 0.34† 0.9* 0.18*
12 (100) 0 0 0 0 0 1 [1] 12 0 5 (41.7) 7 (58.3) 31.5 [6.5] 23 [6.5]
N/A N/A 0.46‡ 0.99‡ 0.58‡ 0.08* 0.80*
< 0.001† < 0.001† < 0.09† < 0.001† < 0.001† N/A N/A N/A N/A N/A
1727 ± 521 12 (100) 1 (8.3) 6 (50) 4 (33.3) 0 0 0 2.7 ± 3.7 0
< 0.001* < 0.001‡ 0.37‡ < 0.001‡ < 0.001‡ N/A N/A N/A N/A N/A
Data presented as mean ± SD, n, n (%) or median [interquartile range]. *Mann–Whitney U-test. †Chi-square test. ‡Fisher’s exact test. §Five in term group and one in preterm group lost to follow-up. N/A, not applicable; PTB, preterm birth; PPROM, preterm prelabor rupture of membranes.
We acknowledge that bacterial vaginosis and fetal fibronectin, two potentially powerful predictors of preterm birth, were not tested in our cohort. A Cochrane review of three trials with 421 participants in total showed that, in women with a previous preterm birth and asymptomatic bacterial vaginosis, antibiotic treatment did not significantly reduce the risk of subsequent preterm birth (absolute risk reduction, 0.78 (95% CI, 0.42–1.48))33 . Therefore, our policy to date has been not to perform bacterial vaginosis screening for asymptomatic women in our preterm labor clinic. Fetal fibronectin testing has shown to be most accurate in predicting imminent spontaneous preterm birth among symptomatic women34 . In a systematic review by Honest et al.34 , the diagnostic accuracy of fetal fibronectin in high-risk asymptomatic women varied greatly. The median likelihood ratio for predicting spontaneous preterm birth before 34 weeks’ gestation among the five highest-quality studies was 3.99 (interquartile range, 1.73–10.18). In our clinic population, with an average pretest probability of preterm birth of 26%, a positive fetal fibronectin test would increase the risk of preterm birth to 58.4%. Although this is certainly
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
promising, this interpretation may not be applicable to a subgroup of high-risk women with a long cervix. The usefulness of fetal fibronectin testing is further limited by the lack of proven successful treatment interventions in this cohort. This is an area that requires further research, and we eagerly await the findings of the OPPTIMUM trial of prophylactic progesterone to prevent preterm birth in fetal fibronectin-positive women35 . Limitations of this study include the relatively small sample size and predominantly White British population demographic. We had been looking for strong associations that are clinically important on an individual patient level in an attempt to identify those women with a long cervix at risk of preterm birth. However, our negative findings may be influenced by the small sample size, and it is possible that these findings would not be replicated in a larger cohort. Additionally caution should be exercised before applying these results to other geographical locations, particularly in areas with a higher representation of Black race, a known risk factor for preterm birth1 . Out of 196 high-risk women screened in our clinic, 12 (6.1%) had a preterm birth before 34 weeks’ gestation,
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Gestational age at delivery (weeks)
45
40
35
30
25 20
30 40 50 Cervical length at 20–24 weeks (mm)
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Figure 2 Scatterplot of midtrimester cervical length measurement against gestational age at delivery in a cohort of 196 women with a history of spontaneous preterm birth or preterm prelabor rupture of membranes before 34 weeks’ gestation.
despite persistently normal cervical length measurements. If we are to make progress in ameliorating the global burden of spontaneous preterm birth, we should move away from a short cervix as the only clinically useful ‘biomarker’ for all pathologies of preterm birth. We need to focus on a better understanding and identification of mechanisms behind the multitude of etiologies causing this syndrome. Only through such research will we be able to develop more effective screening and treatment strategies that could be applied to both high- and low-risk populations. Suggested ways forward would be: (1) to continue with the search for alternative biomarkers in blood, amniotic fluid or vaginal secretions to aid our understanding of pathways of action36 ; (2) to explore genetic association studies, a major tool for identifying genes conferring susceptibility to disorders in which both genetic and environmental factors contribute to susceptibility risk37,38 ; and (3) to understand how to link this new information together to provide individual patient-risk assessment. Until more robust, personalized predictive models are developed, cervical length will remain our best clinical marker in high-risk asymptomatic women. However, for a significant number of high-risk women, a long cervix will provide false reassurance against recurrent preterm birth and its sequelae.
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